Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) is an exemplary 2,3-benzodiazepine molecule. Tofisopam is a non-sedative anxiolytic that has no appreciable sedative, muscle relaxant or anticonvulsant properties (Horvath et al., Progress in Neurobiology, 60 (2000), 309-342). In addition, tofisopam has been employed in the treatment of gastrointestinal disorders, including irritable bowel syndrome, and has been used in the treatment of menopausal symptoms.
Tofisopam is a racemic mixture of (R)- and (S)-enantiomers. The chiral nature of tofisopam is due to the asymmetric carbon, at the 5-position of the benzodiazepine ring, attached with four different groups. Differential therapeutic effects have been noted for either enantiomer. For example, the (R)-enantiomer of tofisopam has been isolated and shown to possess the nonsedative anxiolytic activity of the racemic mixture. See U.S. Pat. No. 6,080,736; the entire disclosure of which is incorporated herein by reference. Furthermore, the (R)-enantiomer has been shown to have a differential effect in the treatment of leukotriene B4-mediated disease. See U.S. Pat. No. 6,864,251; the entire disclosure of which is incorporated by reference. The (S)-enantiomer has been isolated and shown to possess an anticonvulsant activity. See U.S. Pat. No. 6,649,607; the entire disclosure of which is incorporated herein by reference. Similarly, the (S)-enantiomer has been shown to be effective in lowering body temperature, as in minimizing hot flashes. See US Patent Publication 20040229866; the entire disclosure of which is incorporated herein by reference.
Therefore, it is frequently desirable to obtain one enantiomer substantially free of the other enantiomer in high yield. Present methodologies for preparing an isolated enantiomer result in the generation of a large amount of the undesired enantiomer. The present invention converts the undesired enantiomer to the desired enantiomer to increase the yield of the desired enantiomer.